Endovascular magnetic method for targeted drug delivery

ABSTRACT

The method for endovascular magnetic targeting drug delivery in a vascular wall and adjoining tissues, wherein an endovascular mesh stent with paramagnetic properties is preliminary implanted in the area of interest by a catheter, a polymeric magneto-responsive carrying agent in the form of particles, containing a drug, is injected, and a magnetic field is applied, characterized in that, at least, one temporary catheter is introduced in the right atrium, and/or in ventricles of heart, and/or in a coronary sinus and/or in a coronary vein, which distal end takes a position close to the implanted mesh stent, thereupon, a gradient permanent magnetic field is generated and adjusted by means of a permanent magnet and/or a solenoid with the core, connected to an electric power source, which magnet or solenoid are located at the distal end of each temporary catheter, where the maximal gradient of magnetic field is located in the implanted endovascular stent, principally on the stent mesh.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a U.S. National Phase of PCT/RU2006/000496, filed onSep. 26, 2006, the entire contents of which are hereby incorporated byreference.

BACKGROUND OF THE INVENTION

The invention relates to medicine, namely to methods of endovasculardrug therapy, and, in particular, to methods of locally increasing aconcentration of drugs in the walls of arteries and veins, in particularfor prevention of coronary restenosis.

A number of drugs require intravenous or intra-arterial infusion, bypassing the digestive system, so as to preserve the drugs fromdegradation by catalytic enzymes in the digestive tract. Also,application of a drug with high toxicity in high concentration requiresaccurate control of their delivery. Moreover, a delivery agent, notbeing an active pharmacological agent, can still boost the activity ofthe delivered drug by mediation of its therapeutic activity.

At present, the role of a delivery agent is usually played by a stentwith a drug coating. The active substance (paclitaxel, sirolimus,zotarolimus) is dissolved in the polymeric coating of the stent, and isthen gradually released, preventing proliferation of smooth muscle cellsof an arterial wall, thus preventing evolution and occurrence ofrestenosis of the stented arteries. At the same time, the drug elutingstents induce an inflammation and can even result in subsequentthrombosis owing to secondary hypersensitivity in some patients, andalso owing to a slowdown of endothelization process (see N. Malik etal., “Phosphorylcholine-coated stents in porcine coronary arteries: invivo assessment of biocompatibility,” J Invasive Cardiol. 13 (2001), pp.193-201, A. V. Finn et al., “Differential response of delayed healingand persistent inflammation at sites of overlapping sirolimus- orpaclitaxel-eluting stents,” Circulation 112 (2005), pp. 270-278, R.Virmani et al., “Localized hypersensitivity and late coronary thrombosissecondary to a sirolimus-eluting stent: should we be cautious?”Circulation 109 (2004), pp. 701-705). The polymeric coating extends thestage of thrombogenesis and of acute inflammation. All existingintravascular stents used in a clinical practice, have paramagneticproperties, except for diamagnetic nitinol self-expandable stents.

There are alternate ideas of a drug delivery to a vascular wall, inparticular, by using composite super-paramagnetic nanoparticles, theferromagnetic or paramagnetic stents and an exterior magnetic field. Atthe same time, some data are available about negative biological effectson humans of the impact of a permanent magnetic field with the intensityover 1 Tesla (see Y. Kinouchi, “Electromagnetic Mechanisms ofBiomagnetic Effects,” The Journal of the Japanese Society of MagneticApplications in Dentistry, (1997) Vol. 6, No. 1, pp. 13-17). Severalcomprehensive reviews have attempted to postulate human exposure limitsand recommends a level of 0.02 T for continuous exposure. The apparentbasis for the 0.02 T recommendation derives from the fact that lowestexposure level which no effect was reported was 0.008-0.01 T (see E. E.Ketchen et al., “The Biological Effects of Magnetic Fields on Man,” Am.Ind. Hyg. Assoc. J., 39:1-11 (1978) and Z. N. Nakhilnitskaya,“Biological Effects of Permanent Magnetic Fields,” Space Biology andAerospace Medicine, 8(6): 1-25 (1974)). Two general types of effectsfrom exposures to magnetic fields are postulated as a result oftheoretical calculations: magnetomechanical and electromagnetic.Magnetomechanical forces could produce translation and rotation ofparticles (molecules, cells, etc.), and electromagnetic forces couldproduce induced voltages and flow modification.

A magnet-controlled system of the targeted drug delivery to destinationplaces, associated with magneto-sensitive particles (see U.S. PatentPublication No. 2006/0041182), where an intravascular magnetized device(for example, a stent made of a paramagnetic material) is implanted, inadvance, by a catheter, in the area of interest of the blood vessel,then a polymeric magneto-sensitive carrying agent prepared in the formof particles containing a drug, is injected into the blood vessel, andthereafter, a magnetic field from an exterior source is activated,whereby a gradient magnetic field is generated in the area of interestof the blood vessel, attracting particles of the magneto-sensitivecarrying agent.

However, this method cannot be used in organs and vessels with anintensive blood flow. In particular, the aorta and coronary arteries ofheart have such high parameters of volumetric velocity of a blood flow,that particles of the carrying agent with size range 0.01 to 1.0 micronswill only concentrate in the field of interest in case of the magneticfield induction in excess of 1.0 Tesla. This is unpredictable for thecardiac electrophysiology, for functioning of pace-makers of heartrhythm and carries a risk generating life-threatening arrhythmias. Also,the unpredictable Theological effects caused by concentration oferythrocytes are possible in the area in question. For the particlescontaining drug with size range 2 to 10 microns, i.e., comparable tosize of the blood cell components, concentration on magnetosensitiveimplants under the force of an exterior magnetic field can result inmagneto-induced thrombogenesis. Also, a strong exterior permanentmagnetic field has an impact on the central nervous system.

A conventional method of use of a ring catheter (see U.S. Pat. Nos.5,951,566 and 5,851,218), intended for slow expansion of walls atvasoconstriction without blocking a fluid stream and/or the drainage ofsediments on the walls of blood vessels, is known. The method consistsof an introduction of a catheter with a conductor of a magnetic fieldand an inductance coil, and delivery to the area of interest, along withthe catheter, of a stent coated with activatable adhesives and providedwith elements containing permanent magnets. Interacting of magneticfields of the inductance coil and of the permanent magnets allows toexpand the stent and to intensify the process of implantation ofadhesive specimens in the walls of the blood vessel. However, in such anarrangement, the magnetized micro-carrying agents will be attracted toan element with the maximum magnetic intensity, i.e., to the catheterand its components (to the coil core and/or to the ring permanentmagnet), instead of the stent on walls of the blood vessel. Thus, itwill not be possible to use these micro-carrying agents forintensification of treating the walls of the blood vessel with thedrugs. This known method is inapplicable to processing intravascularareas with magneto-sensitive carrying agents containing a drug.

SUMMARY OF THE INVENTION

The claimed invention is intended to eliminate the above drawbacks.

The technical result, achieved by application of the claimed method,consists in increased reliability, efficiency and safety of delivery ofdrugs to a vascular wall and adjoining tissues in the vessels with anintensive stream of blood in the area of implantation of the stent, bothat the time of stent implantation, and at a substantially later time,and in particular, in coronary arteries.

Still another technical result of the claimed method consists inlowering the risk of restenosis of arteries in the area of the implantedstent owing to more effective drug administration.

Also, the proposed method is aimed at controlling concentration of thedrugs in a vascular wall by means of adjustment of the magnetic fieldparameters.

The proposed method includes that, for endovascular delivery of a drugin a vascular wall and adjoining tissues in the area of implantation ofa stent with paramagnetic properties, a polymeric magneto-responsivecarrying agent in the form of particles, containing a drug, is injected.At this moment, a gradient permanent magnetic field is generated andadjusted by means of at least one temporary catheter containing at itsdistal end, a permanent magnet and/or a solenoid with the core,connected to an electric power source, where the temporary catheter isintroduced into the right auricle, and/or into ventricles of heart,and/or into a coronary sinus and/or into a coronary vein, and themaximal gradient of the magnetic induction density is located in thestented arterial segment, thus providing improved settling and deductionof magnetosensitive particles to the inner wall of the blood vessel inthe area of the paramagnetic stent implantation.

It is preferable to use, for efficient control of the magnetic fieldgradient, a solenoid with a core of cylindrical shape, covered by aconical cap, or a permanent magnet of the same shape.

The level of the magnetic induction density of the volumetric gradientmagnetic field is adjusted by varying the electric current parameters inthe solenoid or by selection of proper permanent magnets.

The effective aiming of the magnetic gradient is implemented bycontrolled positioning of the inner magnetic sources regarding thestent. Shaping of a three-dimensional permanent gradient magnetic fieldis also possible.

The stent is made of a paramagnetic material, such as commonly usedparamagnetic alloys: steel 316L, cobalt-chromium alloy, cobalt-nickelalloy, etc. Application of biodegradable stents with paramagneticproperties is also possible.

The size of particles of a polymeric magneto-responsive carrying agentis, preferably within the range 0.01 to 1.0 micron.

At the distal end of the temporary catheter, a cylindrical permanentmagnet with the typical length range 1 to 50 mm is used.

At the distal end of the temporary catheter, a cylindrical solenoid withthe length range 1 to 50 mm can be used, as another alternative.

BRIEF DESCRIPTION OF THE DRAWINGS

For better understanding of the claimed invention, its detaileddescription with corresponding drawings follows.

FIG. 1 shows the conventional method with application of an exteriormagnetic field, where 1 is an exterior source of a magnetic field, hi isthe distance to a stent, which is usually the range of 50 to 100 mm.

FIG. 2 demonstrates one of alternatives for reducing the distance from asource of a magnetic field; in this case the role of such source isplayed by temporary magnetic catheter 3, and stent 4. FIG. 2 showssource 2 of electric current which is necessary in case of using thesolenoid in the temporary magnetic catheter 3. Also, a cardiac vein 6through which the temporary magnetic catheter 3 is introduced, is shownand coronary artery 5, which accommodates stent 4.

FIG. 3 demonstrates reduction of the distance between stent 4 implantedin cardiac artery 5, and temporary magnetic catheter 3 introduced intocardiac vein 6. Here, distance h2 between the source of the magneticfield, i.e., temporary magnetic catheter 3, and stent 4, is within, onthe average, 1 mm.

FIG. 4 presents an alternative method of localization of temporarycatheters 3 and stent 4 at preventive treatment of coronary restenosis,where 7 is a coronary sine, 8 is the right ventricle of a heart, 9 isthe right atrium.

FIG. 5 shows the final stage of the method, where magnetic catheters 3are positioned in ventricles of heart 8 and coronary vein 6 beforehand,and stent 4 is implanted into the coronary artery 5. Suspension 10 ofmagneto-responsive particles through guiding catheter 11 is injected inthe coronary channel, where, under the force of the gradient magneticfield generated by catheter 3, the particles are accumulated in the areaof location of the paramagnetic stent.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

The claimed method is carried out as follows:

Before stent implantation, the catheter (not shown in the figures) isintroduced in that area of the vascular wall which is assigned for thelocal drug treatment affecting, the catheter carries an intravascularmesh implant, i.e., stent 4 made of a paramagnetic material, forexample—steel 316L or other alloys, in particular, cobalt-chromiumalloys, cobalt-nickel alloys, and other materials with paramagneticproperties, and also composite materials. Practically any of stentscommonly used in a clinical practice can be used in this method.

After installation of stent 4 the catheter is removed, and, through theright atrium and coronary sinus 7, at least one temporary catheter 3with the permanent magnet or the solenoid affixed at its distal end isintroduced in coronary vein 6 and/or in right ventricle 8. The role ofsuch permanent magnet is played by a cylindrical or conical piece ofiron, cobalt, nickel, or their alloys, rare earth, magnetic ceramics orpolymers filled with particles of the above materials. It is preferableto use the neodymium permanent magnets (NdBFe). In another alternative,the distal end of catheter 3 can carry a solenoid with a core, connectedto electric power source 2. The core also can have a shape of a cylinderor can be provided with a conical cap, [DISCUSS MORE] and the intensityof the gradient magnetic field is controlled by adjustment of theelectrical current in the solenoid.

Thus, an endovascular source of a gradient permanent magnetic field,temporarily located in cardiac chambers or/and in the cardiac veins, iscreated, thereby distance h2 between the source and stent 4 made ofmagneto-responsive material is substantially reduced and, accordingly,distance between the source and the intravascular area of drugtreatment. Experiments confirmed that the optimal alternative consistsin designing the distal end of the temporary catheter in the shape of acylindrical permanent magnet or a solenoid with length range of 1 to 50mm, thereby achieving an essential decrease (reduction) of workingmagnetic field intensity to the safety level for a patient.

The distance between the distal end of the temporary catheter and theintravascular stent can thus be reduced to 1 mm. Furthermore, themagnetization of the intravascular stent is maintained only duringpresence of the gradient permanent magnetic field with the inductionlevel not exceeding 1 Tesla. By means of the controlled current source,it is possible to control the parameters of the magnetic field inducedby a solenoid in the area of local drug administering, and, accordingly,to control the level of adhesion of drugs to a vascular wall in the areaof implantation of the paramagnetic stent.

At the final stage of the method a magneto-responsive polymeric carryingagent, i.e., the suspension of particles whose size is, preferably,within the range 0.1-1.0 micron, containing a drug, is injected into avascular channel. Under the force of a gradient permanent magneticfield, the magneto-responsive polymeric particles are concentrated inthe area of the stent, thus rendering the targeted drug treatment of thearterial wall, as shown in FIG. 5. The temporary catheters withpermanent magnets or solenoids are then removed, and no residualmagnetization remains on the stent.

Having thus described a preferred embodiment, it should be apparent tothose skilled in the art that certain advantages of the described methodand apparatus have been achieved. It should also be appreciated thatvarious modifications, adaptations, and alternative embodiments thereofmay be made within the scope and spirit of the present invention. Theinvention is further defined by the following claims.

1-13. (canceled)
 14. A method for endovascular magnetic targeting drugdelivery in a vascular wall and adjoining tissues, comprising:implanting an endovascular mesh stent with paramagnetic propertiesimplanted in an area of interest by using a catheter; injecting apolymeric magneto-responsive carrying agent in a form of particles,containing a drug; and introducing at least one temporary catheter intoa right atrium, and/or in ventricles of heart, and/or in a coronarysinus, and/or in a coronary vein, such that a distal end of thetemporary catheter is positioned in proximity to the implantedendovascular mesh stent; generating a magnetic field at the area ofinterest using the temporary catheter; and adjusting the magnetic fieldby means of a permanent magnet and/or a solenoid with the core,connected to an electric power source, wherein the permanent magnetand/or the solenoid is at the distal end of the at least one temporarycatheter, and wherein a maximum magnetic field is at the implantedendovascular mesh stent.
 15. The method of claim 14, wherein themagnetic field is produced by a permanent magnet of a cylindrical shape.16. The method of claim 15, wherein the cylindrical shape has acone-shaped cap.
 17. The method of claim 14, wherein the magnetic fieldhas a strength between 0.001 and 1 Tesla.
 18. The method of claim 14,wherein the magnetic field is produced by a solenoid having a core of acylindrical shape.
 19. The method of claim 14, wherein the solenoid hasa cone-shaped cap.
 20. The method of claim 14, wherein the magneticfield is controlled by the adjusting an electric current through thesolenoid.
 21. The method of claim 14, wherein the endovascular meshstent is made of a paramagnetic material.
 22. The method of claim 14,wherein the endovascular mesh stent is made of a composite biodegradablematerial with paramagnetic properties.
 23. The method of claim 14,wherein the temporary catheter has, at its distal end, a solenoid withlength between 1 and 50 mm.
 24. The method of claim 14, wherein a sizeof particles of the polymeric magneto-responsive carrying agent isbetween 0.01-1.0 microns.
 25. The method of claim 14, wherein thetemporary catheter and the magneto-sensitive agent are introducedimmediately after the endovascular mesh stent implantation.
 26. Themethod of claim 14, wherein the temporary catheter and themagneto-responsive carrying agent are introduced for a drug treatment ofa vascular wall at any time after the endovascular mesh stentimplantation.